Sulfonylaminophosphinic and sulfonylaminophosphonic acid derivatives, methods for their preparation and use

ABSTRACT

Compounds of the formula I  
                 
 
     are suitable for the production of pharmaceuticals for the prophylaxis and therapy of disorders in the course of which an increased activity of matrix-degrading enzymes is involved.

[0001] The invention relates to novel sulfonylaminophosphinic andsulphonylaminophosphonic acid derivatives, processes for theirpreparation and use thereof as pharmaceuticals.

[0002] The present application claims priority under 35 U.S.C. § 119 toGerman applications No. 19831980.0 filed Jul. 16, 1998, and No.19921680.0 filed May 12, 1999. Both priority applications are entirelyincorporated herein by reference.

[0003] The applications EP 0 606 046, WO 95/35276 and WO 96/27583describe arylsulfonamidohydroxamic acids and their action as matrixmetalloproteinase inhibitors. Specific arylsulfonamidocarboxylic acidsare used as intermediates for the preparation of thrombin inhibitors (EP0 468 231) and aldose reductase inhibitors (EP 0 305 947). Theapplication EP 0 757 037 also describes the action ofsulfonylaminocarboxylic acid derivatives as metalloproteinaseinhibitors. The arylsulfonyl group has furthermore proved to be aneffective protective group of the amino function of α-aminocarboxylicacids. R. Roemmele, H. Rapoport, 53 J. ORG. CHEM. 2367 (1988).

[0004] In the attempt to find efficacious compounds for the treatment ofconnective tissue disorders, it has now been found that thesulfonylaminophosphinic and -phosphonic acid derivatives according tothe invention are strong inhibitors of metalloproteinases. Particularvalue is placed here on the inhibition of stromelysin (matrixmetalloproteinase 3, “MMP-3”), of neutrophil collagenase (“MMP-8”) andof aggrecanase, since these enzymes are involved to a considerableextent in the degradation of proteoglycans, as important constituents ofthe cartilaginous tissue. A. J. Fosang et al., 98 J. CLIN. INVEST. 2292(1996).

[0005] The pathological loss of aggrecan, the main proteoglycan of thecartilage, includes proteolytic cleavages in its interglobular domain.Amino acid sequence analyses of proteoglycan metabolites, isolated fromthe synovial fluid of patients who are suffering from injury to a joint,from osteoarthrosis or from an inflammatory joint condition, showed thata proteolytic cleavage preferably takes place between the amino acidsGlu³⁷³ and Ala³⁷⁴ in the interglobular domain of human aggrecan.Lohmander et al., 36 ARTHRITIS RHEUM. 1214 (1993). Until now, it was notyet possible to identify the proteolytic activity which is responsiblefor this cleavage. It is designated as “aggrecanase” and can be includedin the metalloproteinases family.

[0006] The detection of the expression of MT1-MMP in human cartilaginoustissue for the first time (Büttner et al., 40 ARTHRITIS RHEUM. 704(1997)), combined with the proof that the catalytic domain of thisenzyme cleaves at the “aggrecanase” cleavage site in the recombinantaggrecan fusion protein rAgg1_(mut) (Büttner et al., 333 BIOCHEM. J. 159(1998)), led to the testing of the strong matrix metalloproteinaseinhibitors described here with respect to their action against an“aggrecanase” activity. It was possible here to show using various assaysystems that the sulfonylaminophosphinic and -phosphonic acidderivatives are also strong inhibitors for the “aggrecanase” activity.

[0007] The invention therefore relates to the compounds of the formula I

[0008] stereoisomeric forms thereof, and physiologically tolerable saltsthereof, where

[0009] (A.) R¹ is

[0010] 1. phenyl;

[0011] 2. phenyl, which is mono- or disubstituted by

[0012] 2.1. (C₁-C₆)—alkyl,

[0013] 2.2. hydroxyl,

[0014] 2.3. (C₁-C₆)—alkyl—C(O)—O—,

[0015] 2.4. (C₁-C₆)—alkyl—O—,

[0016] 2.5. (C₁-C₆)—alkyl—O—(C₁-C₄)—alkyl—O—,

[0017] 2.6. halogen,

[0018] 2.7. —CF₃,

[0019] 2.8. —CN,

[0020] 2.9. —NO₂,

[0021] 2.10. HO—C(O)—,

[0022] 2.11. (C₁-C₆)—alkyl—O—C(O)—,

[0023] 2.12. methylenedioxo,

[0024] 2.13. R⁴—(R⁵)N—C(O)—,

[0025] 2.14. R⁴—(R⁵)N—, or

[0026] 2.15 a heteroaromatic described under A.3.1 to A.3.16;

[0027] 3. a heteroaromatic described under A.3.1 to A.3.16, which isunsubstituted or substituted by one or more radicals described underA.2.1 to A.2.15,

[0028] 3.1. pyrrole,

[0029] 3.2. pyrazole,

[0030] 3.3. imidazole,

[0031] 3.4. triazole,

[0032] 3.5. thiophene,

[0033] 3.6. thiazole,

[0034] 3.7. oxazole,

[0035] 3.8. isoxazole,

[0036] 3.9. pyridine,

[0037] 3.10. pyrimidine,

[0038] 3.11. pyrrolidine,

[0039] 3.12. indole,

[0040] 3.13. benzothiophene,

[0041] 3.14. benzimidazole,

[0042] 3.15. benzoxazole, or

[0043] 3.16. benzothiazole; or

[0044] 4. —O—(C₁-C₆)—alkyl;

[0045] (B.) R², R⁴ and R⁵ independently of one another are identical ordifferent and are

[0046] 1. a hydrogen atom;

[0047] 2. (C₁-C₆)—alkyl-;

[0048] 3. HO—C(O)—(C₁-C₆)—alkyl-;

[0049] 4. phenyl—(CH₂)n—, in which phenyl is unsubstituted or mono- ordisubstituted with radicals described under A.2.1 to A.2.15, or issubstituted by —NH—C(O)—(C₁-C₃)—alkyl, and n is the integer zero, 1, or2;

[0050] 5. picolyl; or

[0051] 6. R⁴ and R⁵, together with the nitrogen to which they arebonded, form a 4- to 7-membered ring, and the ring is unsubstituted, ora carbon atom in the ring is replaced by —O—, —S—, or —NH—, or twoadjacent carbon atoms of the 4- to 7-membered ring are part of a benzylradical;

[0052] (C.) R and R³ are identical or different and are

[0053] 1. a hydrogen atom;

[0054] 2. (C₁-C₁₀)—alkyl-, in which alkyl is unsubstituted ormonosubstituted by —OH;

[0055] 3. (C₂-C₁₀)—alkenyl-, in which alkenyl is linear or branched;

[0056] 4. R²—O—(C₁-C₆)—alkyl-;

[0057] 5. R²—S(O)_(n)—(C₁-C₆)—alkyl-, where n is the integer zero, 1, or2;

[0058] 6. R²—S(O)(═NH)—(C₁-C₆)—alkyl-;

[0059] 7. a radical of formula IIo

[0060] in which n is the integer zero, 1, or 2, and W is a nitrogen,oxygen, or sulfur atom;

[0061] 8. phenyl—(CH₂)_(m)—, in which m is the integer zero, 1, 2, 3, 4,5, or 6, wherein the —(CH₂)_(m)— chain is unsubstituted ormonosubstituted by —OH, and wherein phenyl is unsubstituted or mono- ordisubstituted by

[0062] 8.1 radicals described under A.2.1 to A.2.15,

[0063] 8.2 —O—(CH₂)_(m)—phenyl, in which phenyl is unsubstituted ormono- or disubstituted with radicals described under A.2.1 to A.2.15,and m is the integer zero, 1, 2, 3, 4, 5, or 6,

[0064] 8.3 —C(O)—(CH₂)_(m)—phenyl, in which phenyl is defined underC.8.2;

[0065] 9. heteroaryl—(CH₂)_(m)—, in which heteroaryl is defined underA.3.1 to A.3.16, m is defined under C.8, the —(CH₂)_(m)— chain isunsubstituted or monosubstituted by —OH, and heteroaryl is unsubstitutedor mono- or disubstituted by

[0066] 9.1 radicals described under A.2.1 to A.2.15,

[0067] 9.2 —CH(O),

[0068] 9.3 —SO₂—phenyl, in which phenyl is unsubstituted or substitutedas defined under C.8.2 or C.8.3,

[0069] 9.4 —O—(CH₂)_(m)—phenyl;

[0070] 10. —(CH₂)_(m)—P(O)(OH)—(C₁-C₃)—alkyl, in which m is definedunder C.8;

[0071] 11. a characteristic radical of an amino acid;

[0072] 12. R⁶—C(O)—(C₀C₆)—alkyl- in which R⁶ is

[0073] 12.1. a hydrogen atom,

[0074] 12.2. (C₁-C₆)—alkyl-,

[0075] 12.3. phenyl, which is unsubstituted or substituted with one ormore radicals described under A.2.1 to A.2.15,

[0076]12.4. heteroaryl, which is defined under A.3.1 to A.3.16, and isunsubstituted or substituted with one or more radicals described underA.2.1 to A.2.15, or is substituted by —(C₁-C₄)—alkyl—COOH,

[0077] 12.5. —OH,

[0078] 12.6. —OR², in which R² has the meaning described under B.1 toB.6,

[0079] 12.7. —NR⁴—(R⁵), in which R⁴ and R⁵ are defined under B.1 to B.6,

[0080] 12.8. heteroaryl—(CH₂)_(m)—NH—, in which heteroaryl is definedunder A.3.1 to A.3.16, and is unsubstituted or substituted with one ormore radicals described under A.2.1 to A.2.15, and m is defined underC.8,

[0081] 12.9. R⁴—(R⁵)N—NH—, in which R⁴ and R⁵ are defined under B.1 toB.6,

[0082] 12.10. HO—C(O)—CH(R³)—NH—, in which R³ is defined under C.1 toC.11;

[0083] 13. —(CH₂)_(p)—N(R⁹)(R¹⁰), in which p is an integer zero, 1, 2,3, or 4, in which R⁹ and R¹⁰ are identical or different and are

[0084] 13.1. a hydrogen atom,

[0085] 13.2. phenyl—(CH₂)_(m)—, in which phenyl is unsubstituted ormono- or disubstituted with radicals described under A.2.1 to A.2.15,and m is the integer zero, 1, 2, or 3,

[0086] 13.3. R^(x)—C(O)—, in which R^(x) is

[0087] 3.1 (C₁-C₆)—alkyl-,

[0088] 3.2 (C₂-C₆)—alkenyl-,

[0089] 3.3 phenyl—(CH₂)_(m)—, in which phenyl is unsubstituted or mono-or disubstituted with radicals described under A.2.1 to A.2.15, and m isthe integer zero, 1, 2, or 3, or

[0090] 3.4 heteroaryl—(CH₂)_(m)—, in which heteroaryl is defined underA.3.1 to A.3.16,

[0091] 13.4. R^(x)—O—C(O)—, in which R^(x) is defined under C.13.3,

[0092] 13.5. R^(x)—CH(NH₂)—C(O)—, in which R^(x) is defined underC.13.3,

[0093] 13.6. R⁸—N(R⁷)—C(O)—, in which R⁸ is

[0094] 6.1 a hydrogen atom

[0095] 6.2 (C₁-C₆)—alkyl-,

[0096] 6.3 phenyl—(CH₂)_(m), in which phenyl is unsubstituted or mono-or disubstituted with radicals described under A.2.1 to A.2.15, and m isthe integer zero, 1, 2, or 3, or

[0097] 6.4 heteroaryl—(CH₂)_(m), in which heteroaryl is defined underA.3.1 to A.3.16, and is unsubstituted or substituted with one or moreradicals described under A.2.1 to A.2.15, m is the integer zero, 1, 2,or 3, and in which R⁷ is a hydrogen atom or (C₁-C₆)—alkyl-, or in whichR⁷ and R⁸, together with the nitrogen atom to which they are bonded,form a 4- to 7-membered ring, and the ring is unsubstituted or a carbonatom in the ring is replaced by —O—, —S—, or —NH—,

[0098] 13.7. R^(x)—SO₂—, in which R^(x) is defined under C.13.3,

[0099] 13.8. R^(x)—NH—C(═NR⁷)—, in which R^(x) is defined under C.13.3and R⁷ is defined under C.13.6.4, or R^(x) and R⁷ are

[0100] 8.1 (C₁-C₆)—alkyl—C(O)—,

[0101] 8.2 —NO₂ or

[0102] 8.3 —SO₂—(CH₂)_(q)—phenyl, in which phenyl is unsubstituted ormono- or disubstituted with radicals described under A.2.1 to A.2.15,and q is the integer zero, 1, 2, or 3,

[0103] 13.9. —SO₂—(CH₂)_(q)—phenyl-phenyl, in which each phenylindependently is unsubstituted or mono- or disubstituted with radicalsdescribed under A.2.1 to A.2.15, and q is the integer zero, 1, 2, or 3,or

[0104] 13.10. a radical of formula IIp

[0105] in which m is the integer zero, 1, 2, or 3, and W is a nitrogenatom or sulfur atom, or

[0106] R⁹ and R¹⁰, together with the nitrogen atom to which they arebonded, form a ring chosen from radicals of the subformulae IIa to IIn,

[0107] where r is the integer 1 or 2, R¹¹ is a radical described underA.2.1 to A.2.15, R⁷ is defined under C.13.6.4, and m is defined underC.13.2, and a carbon atom in the ring is replaced by zero or oneheterospecies chosen from oxygen, sulfur, or nitrogen atom which isunsubstituted or monosubstituted with R²;

[0108] 14. —OH;

[0109] 15. ═O;

[0110] 16. (C₁-C₆)—alkyl-; or

[0111] in the compound of formula I, a —C(R)(R³)— radical is optionallyreplaced by —NH— or —NR²— in which R² is defined under B.1 to B.6;

[0112] (D.) t is an integer 1, 2, 3, or 4;

[0113] (E.) R² and R³ together form a ring with an exocyclic phosphinicor phosphonic acid radical of the subformula II

[0114] in which r is the integer zero, 1, 2, or 3, and one carbon atomin the ring of the radical of subformula II is replaced by zero or oneheterospecies chosen from —O—, —S—, or —(R⁷)N—, in which R⁷ is

[0115] 1. a hydrogen atom;

[0116] 2. (C₁-C₆)—alkyl;

[0117] 3. phenyl, in which phenyl is unsubstituted or substituted withone or more radicals described under A.2.1 to A.2.15;

[0118] 4. benzyl, in which benzyl is unsubstituted or substituted withone or more radicals described under A.2.1 to A.2.15; or

[0119] 5. R²N—C(═NH)— where R² has the meaning described under B.1 toB.6, and the carbon atoms in the ring of the subformula II areunsubstituted or mono- or polysubstituted by (C₁-C₆)—alkyl-, phenyl-,phenyl—(CH₂)_(m)— or HO—, or combinations thereof;

[0120] (F.) U is —SO₂— or —CO—;

[0121] (G.) Y¹ and Y² are identical or different and independently ofone another are

[0122] a) a hydrogen atom;

[0123] b) —OH;

[0124] c) —(C₁-C₄)—alkyl, in which alkyl is linear or branched;

[0125] d) —(CH₂)_(u)—phenyl, in which u is zero or 1;

[0126] e) —O—(C₁-C₄)—alkyl, in which alkyl is linear or branched; or

[0127] f) —O—(CH₂)_(s)—phenyl, in which s is zero or 1;

[0128] (H.) A is

[0129] a) a covalent bond;

[0130] b) —O—;

[0131] c) —CH═CH—; or

[0132] d) —C≡C—;

[0133] (I.) B is

[0134] a) —(CH₂)_(m)—, in which m is defined under C.13.2;

[0135] b) —O—(CH₂)_(p), in which p is an integer from 1 to 5; or

[0136] c) —CH═CH—; and

[0137] (J.) X is —CH═CH—, an oxygen atom, or a sulfur atom.

[0138] A preferred compound of the formula I is one where

[0139] R¹ is

[0140] 1. phenyl;

[0141] 2. phenyl which is monosubstituted by

[0142] 2.1. (C₁-C₅)—alkyl-,

[0143] 2.2. —OH,

[0144] 2.3. —C(O)—OH,

[0145] 2.4. —O—(C₁-C₆)—alkyl,

[0146] 2.5. pyrrolidone,

[0147] 2.6. halogen, or

[0148] 2.7. —CF₃; or

[0149] 3. —O—(C₁-C₆)—alkyl;

[0150] R², R⁴ and R⁵ are identical or different and are a hydrogen atomor (C₁-C₆)—alkyl-;

[0151] R is a hydrogen atom;

[0152] R³ is

[0153] 1. (C₁-C₆)—alkyl-, in which alkyl is unsubstituted ormonosubstituted by —OH,

[0154] 2. R²—S(O)_(n)—(C₁-C₆)—alkyl-, in which R² is (C₁-C₆)—alkyl- orphenyl—(CH₂)_(n)—, and n is the integer zero or 1;

[0155] 3. —(CH₂)_(m)—phenyl, in which phenyl is unsubstituted or mono-or disubstituted with radicals described under A.2.1 to A.2.15 in theoriginal definition of the compound of formula I, the —(CH₂)_(m)— chainis unsubstituted or monosubstituted by —OH, and m is the integer 1, 2,3, 4, or 5;

[0156] 4. —(CH₂)_(m)—heteroaryl, in which heteroaryl has the meaningmentioned under A.3.3, A.3.5, A.3.6, A.3.9, or A.3.11 in the originaldefinition of the compound of formula I, and is unsubstituted orsubstituted with one or more radicals described under A.2.1 to A.2.15 inthe original definition of the compound of formula I, the —(CH₂)_(m)—chain is unsubstituted or monosubstituted by —OH, and m is the integer1, 2, 3, or 4;

[0157] 5. a characteristic radical of an amino acid;

[0158] 6. —(CH₂)_(p)—N(R⁹)(R¹⁰), in which p is the integer zero, 1, or 2in which R⁹ and R¹⁰ are identical or different and are a hydrogen atomor —SO₂—(CH₂)_(q)—phenyl-phenyl, in which each phenyl independently isunsubstituted or mono- or disubstituted with radicals described underA.2.1 to A.2.15 in the original definition of the compound of formula I,and q is the integer zero, 1, 2, or 3; or

[0159] 7. R⁶—C(O)—, in which R⁶ is

[0160] 7.1. —OH,

[0161] 7.2. R²O—, in which R² is defined under B.1 to B.6 in theoriginal definition of the compound of formula I, or

[0162] 7.3. R⁴—(R⁵)N—, in which R⁴ and R⁵ are defined under B.1 to B.6in the original definition of the compound of formula I;

[0163] 8. a hydrogen atom;

[0164] 9. —OH;

[0165] 10. ═O; or

[0166] 11. (C₁-C₆)—alkyl-; or

[0167] in the compound of formula I, a —C(R)(R³)— radical is optionallyreplaced by —NH— or —NR²—, in which R² is defined under B.1 to B.6 inthe original definition of the compound of formula I; and

[0168] t is an integer 1, 2, 3, or 4;

[0169] U is —SO₂—;

[0170] Y¹ is —OH;

[0171] Y² is a) —O—(C₁-C₄)—alkyl, in which alkyl is linear or branched,

[0172] b) —OH, or

[0173] c) —(C₁-C₄)—alkyl, in which alkyl is linear or branched;

[0174] A is a covalent bond or —O—;

[0175] B is a covalent bond or —(C₁-C₄)—alkyl; and

[0176] X is —CH═CH—.

[0177] A particularly preferred compound of the formula I is one where

[0178] R¹ is phenyl which is monosubstituted by halogen;

[0179] R² is a hydrogen atom;

[0180] R is a hydrogen atom;

[0181] R³ is

[0182] 1. (C₁-C₄)—alkyl-;

[0183] 2. -phenyl, in which phenyl is unsubstituted or mono- ordisubstituted by —CF₃ or —COOH;

[0184] 3. a hydrogen atom;

[0185] 4. —OH; or

[0186] 5. —NH—SO₂—phenyl-phenyl, in which each phenyl independently isunsubstituted or substituted by one ore more identical or differenthalogen atoms;

[0187] t is an integer 1, 2, 3, or 4;

[0188] U is —SO₂—;

[0189] Y¹ and Y² are identical or different and are —OH or —O—CH₃;

[0190] A is a covalent bond;

[0191] B is a covalent bond or —(CH₂)_(o)—, in which o is 1, 2, or 3;and

[0192] X is CH═CH—.

[0193] Particularly preferred compounds are (R)—[1-(440-chlorobiphenyl-4-sulfonyl-amino)-2-methylpropyl]phosphonic acid,dimethyl[3-(4′-chlorobiphenyl-4-sulfonylamino)-1-hydroxy-3-(4-trifluoromethylphenyl)propyl]phosphonate,[1-(4′-chlorobiphenyl4-sulfonylamino)-3-methylbutyl]phosphonic acid,stereoisomeric forms thereof, and physiologically tolerable salts of anyof the foregoing.

[0194] The expression “R⁴ and R⁵ together with the ring amino group forma 4- to 7-membered ring and/or one of the carbon atoms is replaced by—O—, —S— or —NH—” is understood as meaning radicals which are derived,for example, from azetidine, pyrrole, pyrroline, pyridine, azepine,piperidine, oxazole, isoxazole, imidazole, indoline, pyrazole, thiazole,isothiazole, diazepine, thiomorpholine, pyrimidine or pyrazine. The term“halogen” is understood as meaning fluorine, chlorine, bromine oriodine. The term “alkyl” or “alkenyl” is understood as meaninghydrocarbon radicals whose hydrocarbon chains are linear, branched, orcyclic, unless otherwise indicated. Cyclic alkyl radicals are, forexample, 3- to 6-membered monocyclic systems such as cyclopropyl,cyclobutyl, cyclopentyl or cyclohexyl. The alkenyl radicals canfurthermore also contain a number of double bonds.

[0195] When a radical is multisubstituted with other radicals, saidother radicals are understood to be independently chosen, beingidentical or different from each other. For example, in the phrase “aheteroaromatic . . . which is unsubstituted or substituted by one ormore radicals described under A.2.1 to A. 2.15,” it is intended thatsaid radicals may be mixed and matched, with the identity of one radicalhaving no bearing on the identity of another. Similarly, when a radicalis disubstituted with other radicals, said other radicals are identicalor different.

[0196] The general structural formula of α-amino acids is as follows:

[0197] The α-amino acids differ from one another by the radical R, whichin the context of the present application is designated as a“characteristic radical” of an amino acid.

[0198] The starting substances for the chemical reactions are known orcan be easily prepared by methods known from the literature. Theaminophosphinic and -phosphonic acids used as starting substances forthe synthesis of the compounds according to the invention are, if notcommerically obtainable in the individual case, synthesizable accordingto known methods (R. S. Rogers, M. K. Stern, SYNLETT, 708 (1992); P. P.Giannousis, P. A. Bartlett, 30 J. MED. CHEM. 1603 (1987); J. P. Genet,M. Uziel, A. M. Touzin, S. Roland, S. Thorimbert, S. Tanier, 33TETRAHEDRON LETT. 77 (1992); E. K. Baylis, C. D. Campbell, J. G.Dingwall, 1 J. CHEM. SOC. PERKIN TRANS. 2845 (1984)).

[0199] The invention furthermore relates to a process for thepreparation of the compounds of the formula I and/or a stereoisomericform of the compounds of the formula I and/or of a physiologicallytolerable salt of the compounds of the formula I, which comprises

[0200] a) reacting an aminophosphinic or -phosphonic acid of the formulaIII

[0201] in which R², Y¹, Y², R, and R³ are as defined in formula I, witha sulfonic acid or carbonyl derivative of the formula IV

[0202] in which R¹, A, X, U, and B are as defined in formula I and Z isa halogen atom, imidazolyl or —OR⁸, in which R⁸ is a hydrogen atom,(C₁-C₆)—alkyl, phenyl or benzyl, wherein said alkyl, phenyl, or benzylis independently unsubstituted or substituted, in the presence of a baseor optionally of a dehydrating agent to give a compound of the formulaI, or

[0203] b) reacting an aminophosphinic or -phosphonic acid ester of theformula (V)

[0204] in which R², R³, t, Y² and R⁸ have the abovementioned meaning,with a sulfonic acid or carbonyl derivative of the formula IV to give acompound of the formula VI

[0205] and converting the compound of the formula VI with removal of theradical R⁸, preferably in the presence of a base or acid, into acompound of the formula I, or

[0206] c) reacting the compound of the formula VII

[0207] where n is the integer zero, 1 or 2, with the aid of a protectivegroup E to give a compound of the formula VIII

[0208] and converting the compound of the formula VIII, using a compoundof the formula IV into a compound of the formula IX

[0209] and then converting the compound of the formula IX, with removalof the protective group E and of the radical R⁸ with the aid of suitablecleavage reagents, into the compound of the formula I, or

[0210] d) separating a compound of the formula I prepared by one of theprocesses a), b) or c), which on account of its chemical structureoccurs in enantiomeric forms, into the pure enantiomers by saltformation with enantiomerically pure acids or bases, chromatography onchiral stationary phases or derivatization by means of chiralenantiomerically pure compounds such as amino acids, separation of thediastereomers thus obtained, and removal of the chiral auxiliary groups,or

[0211] e) isolating the compound of the formula I prepared by one of theprocesses a), b), c) or d) either in free form or, in the case of thepresence of acidic or basic groups, converting it into physiologicallytolerable salts.

[0212] Suitable protective groups E used for this are preferably theN-protective groups customary in peptide chemistry, for exampleprotective groups of the urethane type, benzyloxycarbonyl (Z),t-butoxycarbonyl (“Boc”), 9-fluorenylmethoxycarbonyl (“Fmoc”),allyloxycarbonyl (“Aloc”) or of the acid amide type, in particularformyl, acetyl or trifluoroacetyl, and of the alkyl type, for examplebenzyl.

[0213] Compounds of the formula III employed, in which R² is a hydrogenatom and R³ is the characteristic radical of an amino acid, arepreferably the characteristic radicals of the following naturallyoccurring α-amino acids: glycine, alanine, valine, leucine, isoleucine,phenylalanine, tyrosine, tryptophan, serine, threonine, cysteine,methionine, asparagine, glutamine, lysine, histidine, arginine, glutamicacid and aspartic acid. Compounds of the formula III employed, in whichR² is a hydrogen atom and R³ is the characteristic radical of an aminoacid, are preferably the characteristic radicals, for example, of thefollowing non-naturally occurring amino acids: 2-aminoadipic acid,2-aminobutyric acid, 2,4-diaminobutyric acid, 2-aminoisobutyric acid,2,3-diaminopropionic acid, 1,2,3,4-tetrahydroisoquinoline-1-carboxylicacid, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, 2-amino-pimelicacid, phenylglycine, 3-(2-thienyl)alanine, 3-(3-thienyl)alanine,2-(2-thienyl)glycine, 2-aminoheptanoic acid, pipecolic acid,hydroxylysine, sarcosine, N-methylisoleucine, 6-N-methyllysine,N-methylvaline, norvaline, norleucine, omithine, alloisoleucine,allothreonine, 4-hydroxyproline, 3-hydroxyproline, allohydroxylysine,3-(2-naphthyl)alanine, 3-(1-naphthylalanine), homophenylalanine,homocysteine, homocysteic acid, homotryptophan, cysteic acid,3-(2-pyridyl)alanine, 3-(3-pyridyl)alanine, 3-(4-pyridyl)alanine,citrulline, phosphinothricin, 4-fluorophenylalanine,3-fluorophenylalanine, 2-fluorophenylalanine, 4-chlorophenylalanine,4-nitrophenylalanine, 4-aminophenylalanine, cyclohexylalanine,5-fluorotryptophan, 5-methoxytryptophan, methionine sulfone, methioninesulfoxide or NH₂—NH—CONH₂, if appropriate substituted. In the case ofnaturally but also of non-naturally occurring amino acids which have afunctional group such as amino, hydroxyl, carboxyl, mercapto, guanidyl,imidazolyl or indolyl in the side chain R³, this group can also beprotected.

[0214] If there is an imidazole radical in R³, the sulfonic acidderivative of the formula IV employed for the sulfonamide formation, forexample, serves as a protective group for the imidazole nitrogen, whichcan be removed again, in particular in the presence of bases such assodium hydroxide solution.

[0215] To prepare compounds of the formula I in which R² and R³ togetherform a ring of the substructure II, the starting substances of theformula III utilized are, for example, 2-methylpropylphosphonic acid,piperidine-2-phosphonic acid, piperazine-2-phosphonic acid orhexahydropyridazine-3-phosphonic acid, it being possible, in particular,for the nitrogen in the 4-position of the piperazine-2-phosphonic acidto be substituted by a protective group Z, for example benzyloxycarbonylor tert-butoxycarbonyl as described in process variant c) or by aradical R⁷.

[0216] Starting materials used for the preparation of the sulfonic acidderivatives of the formula IV are preferably sulfonic acids or theirsalts of the formula X, for example

[0217] where R⁹ is a radical described under 2.1. to 2.15.

[0218] For the preparation of the arylsulfonic acids of the formulae Xaand b, the sulfonation process using concentrated sulfuric aciddescribed in Houben-Weyl, METHODEN DER ORGANISCHEN CHEMIE [METHODS OFORGANIC CHEMISTRY] Volume 9, pp. 450-546 is preferably used, ifappropriate in the presence of a catalyst, sulfur trioxide and itsaddition compounds or halosulfonic acids, such as chlorosulfonic acid.Particularly in the case of the diphenyl ethers of the formula Xb, theuse of concentrated sulfuric acid and acetic anhydride as a solvent (cf.C. M. Suter, 53 J. AM. CHEM. SOC. 1114 (1931)), or the reaction withexcess chlorosulfonic acid (J. P. Bassin, R. Cremlyn and F. Swinbourne,72 PHOSPHORUS, SULFUR AND SILICON 157 (1992)) has proven suitable.Sulfonic acids according to the formula Xc, Xd or Xe can be prepared ina manner known per se by reacting the corresponding arylalkyl halidewith sulfites such as sodium sulfite or ammonium sulfite in aqueous oraqueous/alcoholic solution, it being possible to accelerate the reactionin the presence of tetraorganoammonium salts such as tetrabutylammoniumchloride.

[0219] Sulfonic acid derivatives according to formula IV used are, inparticular, the sulfonyl chlorides. For their preparation, thecorresponding sulfonic acids, also in the form of their salts, such assodium, ammonium or pyridinium salts, are reacted in a known manner withphosphorus pentachloride or thionyl chloride without or in the presenceof a solvent such as phosphorus oxychloride or of an inert solvent suchas methylene chloride, cyclohexane or chloroform, in general at reactiontemperatures from 20° C. up to the boiling point of the reaction mediumused.

[0220] The reaction of the sulfonic acid derivatives of the formula IVwith the aminophosphonic acids of the formulae III, V or VII accordingto process variants a), b) or c) proceeds advantageously in the mannerof the Schotten-Baumann reaction. Suitable bases for this areparticularly alkali metal hydroxides such as sodium hydroxide, but alsoalkali metal acetates, hydrogencarbonates, carbonates and amines. Thereaction takes place in water and/or in a water-miscible or immisciblesolvent such as tetrahydrofuran (“THF”), acetone, dioxane oracetonitrile, the reaction in general being kept at from −10° C. to 50°C. If the reaction is carried out in an anhydrous medium,tetrahydrofuran or methylene chloride, acetonitrile or dioxane in thepresence of a base, such as triethylamine, N-methylmorpholine, N-ethyl-or diisopropylethylamine, is especially used, possibly in the presenceof N,N-dimethylaminopyridine as a catalyst.

[0221] In another variant, the aminocarboxylic acids of the formula III,IV or VII can first be converted into their silylated form with the aidof a silylating agent such as bistrimethylsilyltrifluoroacetamide(“BSTFA”) and they can then be reacted with sulfonic acid derivatives togive the compounds of the formula I.

[0222] The preparation of physiologically tolerated salts from compoundsof the formula I capable of salt formation, including theirstereoisomeric forms, is carried out in a manner known per se. Thephosphonic or phosphinic acids form stable alkali metal, alkaline earthmetal or optionally substituted ammonium salts with basic reagents suchas hydroxides, carbonates, hydrogencarbonates, alcoholates and alsoammonia or organic bases, for example trimethyl- or triethylamine,ethanolamine or triethanolamine or alternatively basic amino acids, forexample lysine, ornithine or arginine. If the compounds of the formula Ihave basic groups, stable acid addition salts can also be prepared usingstrong acids. Both inorganic and organic acids such as hydrochloric,hydrobromic, sulfuric, phosphoric, methanesulfonic, benzenesulfonic,p-toluenesulfonic, 4-bromo-benzenesulfonic, cyclohexylamidosulfonic,trifluoromethylsulfonic, acetic, oxalic, tartaric, succinic ortrifluoroacetic acid are suitable for this.

[0223] The invention also relates to pharmaceuticals comprising anefficacious amount of at least one compound of the formula I and/or of aphysiologically tolerable salt of the compound of the formula I and/oran optionally stereoisomeric form of the compound of the formula I,together with a pharmaceutically suitable and physiologically tolerableexcipient, additive and/or other active compounds and auxiliaries.

[0224] On account of the pharmacological properties, the compoundsaccording to the invention are suitable for the prophylaxis and therapyof all those disorders in the course of which an increased activity ofmatrix-degrading enzymes such as metalloproteinases or aggrecanase isinvolved. These include degenerative joint disorders such asosteoarthroses, spondyloses, chondrolysis after joint trauma orrelatively long joint immobilization after meniscus or patella injuriesor torn ligaments. These furthermore also include disorders of theconnective tissue such as collagenoses, periodontal disorders, woundhealing disorders and chronic disorders of the locomotory apparatus suchas inflammatory, immunologically or metabolically related acute andchronic arthritis, arthropathies, myalgias and disorders of the bonemetabolism. The compounds of the formula I are furthermore suitable forthe treatment of ulceration, atherosclerosis and stenoses. The compoundsof the formula I are furthermore suitable for the treatment ofinflammations, carcinomatous disorders, tumor metastasis formation,cachexia, anorexia and septic shock. In general, the pharmaceuticalsaccording to the invention are administered orally or parenterally.Rectal or transdermal administration is also possible.

[0225] The invention also relates to a process for the production of apharmaceutical, which comprises bringing at least one compound of theformula I into a suitable administration form using a pharmaceuticallysuitable and physiologically tolerable excipient and, if appropriate,further suitable active compounds, additives or auxiliaries.

[0226] Suitable solid or pharmaceutical preparation forms are, forexample, granules, powders, coated tablets, tablets, (micro)capsules,suppositories, syrups, juices, suspensions, emulsions, drops orinjectable solutions and preparations with protracted release of activecompound in the production of which customary auxiliaries such asexcipients, disintegrants, binding agents, coating agents, swellingagents, glidants or lubricants, flavorings, sweeteners and solubilizersare used. Frequently used auxiliaries which may be mentioned aremagnesium carbonate, titanium dioxide, lactose, mannitol and othersugars, talc, lactoprotein, gelatin, starch, cellulose and itsderivatives, animal and vegetable oils such as cod liver oil, sunflower,groundnut or sesame oil, polyethylene glycol and solvents such as, forexample, sterile water and mono- or polyhydric alcohols such asglycerol.

[0227] The pharmaceutical preparations are preferably prepared andadministered in dose units, each unit containing as active constituent aspecific dose of the compound of the formula I according to theinvention. In the case of solid dose units such as tablets, capsules,coated tablets or suppositories, this dose can be up to approximately1000 mg, but preferably approximately 50 to 300 mg, and in the case ofinjection solutions in ampoule form up to approximately 300 mg, butpreferably approximately 10 to 100 mg.

[0228] For the treatment of an adult patient weighing approximately 70kg, depending on the efficacy of the compound according to formula I,daily doses of approximately 20 mg to 1000 mg of active compound,preferably, for example, 100 mg to 500 mg, are indicated. Under certaincircumstances, however, higher or lower daily doses may also beappropriate. The daily dose can be administered both by singleadministration in the form of an individual dose unit or else of anumber of smaller dose units and by multiple administration ofsubdivided doses at specific intervals.

[0229]¹H-NMR spectra have been recorded on a 400 MHz apparatus fromBruker or a 200 MHz apparatus from Varian, as a rule usingtetramethylsilane (“TMS”) as an internal standard and at roomtemperature (“RT”). The solvents used are indicated in each case. As arule, final products are determined by mass-spectroscopic methods (FAB-,ESI-MS); the main peak is indicated in each case. Temperatures indegrees Celsius, RT means room temperature (22° C. to 26° C.).Abbreviations used are either explained or correspond to the customaryconventions.

EXAMPLE 1

[0230](R)-[1-(4′-Chlorobiphenyl-4-sulfonylamino)-2-methylpropyl]-phosphonicacid

[0231] 250 mg (1.6 mmol) of (R)-(1-amino-2-methylpropyl)phosphonic acidwere dissolved in 6 ml of a 1 M NaOH and 6 ml of tetrahydrofuran. 560 mg(1.96 mmol) of 4-chlorobiphenyl-4′-sulfonyl chloride were then added andthe mixture was stirred at 22° C. overnight. The reaction mixture wasconcentrated, acidified with 2 M HCl and extracted with ethyl acetate.The 4-chlorobiphenyl4′-sulfonic acid resulting as a by-productprecipitated and was separated off. After drying and concentrating theethyl acetate phase, a solid was obtained.

[0232] Yield: 136 mg (21%); molecular mass: 403.83 ¹H-NMR: in DMSO-d6;10.8 (s,br, 2 H); 7.91; 7.82; 7.76; 7.63 7.56 (5 d, 9 H); 3.06 (m, 1 H);1.98 (m, 1 H); 0.87; 0.80 (dd, 6 H); MS (ESI; M+Na⁺): 425.9

EXAMPLE 2

[0233] Monoethyl(R,S)-[1-(4′-chlorobiphenyl-4-sulfonylamino)-1-phenylmethyl]phosphonate

[0234] 830 mg (3.85 mmol) of monoethyl(R,S)-(aminophenylmethyl)phosphonate were dissolved in 6 ml of 2 M NaOHand 10 ml of tetrahydrofuran. 1.44 g (5.01 mmol) of4-chlorobiphenyl4′-sulfonyl chloride were then added and the mixture wasstirred at 22° C. overnight. The resultant precipitate was separated offand dispersed in hot water/ethyl acetate. After acidifying with HCl topH 1 to 2, the ethyl acetate phase was separated off and concentrated. Asolid remained.

[0235] Yield: 610 mg (34%); molecular mass: 465 ¹H-NMR: in DMSO-d6; 8.66(s, br, 1 H); 7.57 (m, 9 H); 7.16 (m, 2 H); 7.01 (m, 3 H); 4.58 (dd, 1H) 3.85 (m, 2 H); 1.11 (m, 3 H); MS (FAB; M⁺, M+Na⁺): 466.0; 488.0

EXAMPLE 3

[0236](R,S)-[(4′-Chlorobiphenyl-4-sulfonylamino)phenylmethyl]-phosphonic acid

[0237] 320 mg (0.69 mmol) of the monoethyl ester from Example 2 weredissolved in 6 ml of dichloromethane and treated at 0° C. with 0.36 ml(2.75 mmol) of trimethylsilyl bromide. After 4 h at RT, the reactionmixture was concentrated to dryness on a rotary evaporator and theresidue which remained was taken up in water. Solids were removed andthe aqueous phase was freeze-dried.

[0238] Yield: 257 mg (80%); molecular mass: 436.8 g/mol ¹H-NMR: DMSO-d₆;7.6 (m, 8 H); 7.2 (m, 2 H); 7.0 (m, 3 H); 4.2 (m, 1 H) MS (ESI⁻): 436.0

EXAMPLE 4

[0239] (R,S)-[1-(4′-Chlorobiphenyl-4-sulfonylamino)-2-(1H-indol-3-yl)-ethyl]phosphonic acid

[0240] 150 mg (0.274 mmol) of the corresponding diethyl ester weredissolved in 4 ml of dichloromethane and treated at room temperaturewith 0.11 ml (0.82 mmol) of trimethylsilyl bromide. After 3 h, thereaction mixture was concentrated to dryness on a rotary evaporator, theresidue which remained was treated with diisopropyl ether and the solidwas removed by filtration.

[0241] Yield: 42 mg (33%); molecular mass: 490.92 ¹H-NMR: DMSO-d₆; 10.4(s, 2 H); 7.9; 7.68; 7.55 (3 d, 5 H); 7.3; 6.9 (2 m, 8 H); 3.7 (m, 1 H);3.2-2.6 (2 m, 4 H); MS (ESI⁺): 491.0

EXAMPLE 5

[0242] (R,S)-[1-(4′-Chlorobiphenyl-4-sulfonylamino)ethyl]phosphonic acid

[0243] 733 mg (2.8 mmol) of N,O-bistrimethylsilyltrifluoroacetamide wereadded under nitrogen to 178 mg (1.4 mmol) of (R,S)-1-aminoethylphosphonic acid in 30 ml of acetonitrile and the mixture was heatedunder reflux for 2 h. After cooling to 15° C., 490 mg (1.7 mmol) of4′-chlorobiphenyl4-sulfonyl chloride in 15 ml of acetonitrile wereadded. The mixture was stirred at RT for 3 h, concentrated, treated withmethanol and concentrated again.

[0244] The residue was chromatographed on silica gel using methylenechloride/methanol 75:25 and 1% acetic acid.

[0245] Yield: 60 mg (11%), molecular mass: 375.77 ¹H-NMR: DMSO-d₆;1.0-1.2 (m, 3 H), 3.35-3.55 (m, 1 H), 7.5 (d, 2 H), 7.68 (d, 2 H), 7.8(d, 2 H), 8.0 (d, 2 H); MS (ESI⁻): 374.1

EXAMPLE 6

[0246](R,S)-[1-(4′-chlorobiphenyl-4-sulfonylamino)-3-methylbutyl]-phosphonicacid

[0247] 516 mg (2 mmol) of N,O-bistrimethylsilyltrifluoroacetamide wereadded under nitrogen to 222 mg (1 mmol) of(R,S)-1-amino-3-methylbutylphosphonic acid hydrochloride in 30 ml ofacetonitrile and the mixture was heated under reflux for 2 h. Aftercooling to 15° C., 345 mg (1.2 mmol) of 4′-chlorobiphenylsulfonylchloride in 15 ml of acetonitrile were added. The mixture was stirredfor 3.5 h at RT, concentrated, treated with methanol and concentrated.The residue was chromatographed on RP18 using acetonitrile/water(contains 0.1% trifluoracetic acid), gradient 10% to 100% acetonitrile.

[0248] Yield: 75 mg (18%), molecular mass: 417.85; MS (ESI⁻): 416.1

[0249] The compounds defined in Table 1 below were prepared analogouslyto Examples 1 to 6. TABLE 1 Ex. Structure ¹H-NMR M⁺ or M⁻ 1

see text see text 2

see text see text 3

see text see text 4

see text see text 5

see text see text 6

see text see text 7

09-1.15 (m, 6H), 3.65-4.1 (m, 2H), 7.5-8.0 (m, 10H) 447.1 (+) 8

1.85-2.1 (m, 2H), 2.8-3.0 (m, 1H), 4.45-4.75 (m, 1H), 6.98-7.18 (m, 5H),7.5-7.75 (m, 8H), 8.35 (m, 1H) 480.1 (−) 9

1.8-2.0 (m, 2H), 3.1-3.3 (m, 1H), 3.4-3.7 (2xd, 3H), 4.55-4.75 (m, 1H),7.0-7.15 (m, 5H), 7.4-7.65 (m, 8H) 494.1 (−) 10

1.8-2.1 (m, 2H), 3.05-3.25 (m, 1H), 3.5-3.7 (6H), 4.45-4.65 (m, 1H),5.5-6.1 (b, 1H), 7.3 (d, 2H), 7.35-7.7 (m, 10H), 8.4-8.7 (b, 1H) 578.1(+) 11

1.07-1.32 (3H), 1.8-2.15 (m, 2H), 2.75-2.95 (m, 1H), 4.5-4.78 (m, 1H),5.25-5.6 (b, 1H), 7.2 (m, 2H), 7.42-7.72 (m, 10H), 8.5 (t, 1H) 522.1 (−)12

1.55-1.75 (m, 1H), 1.8-2.05 (m, 1H), 3.8-4.0 (m, 1H), 7.55 (d, 2H), 7.75(d, 2H), 7.78-7.85 (m, 4H), 8.0-8.2 (b, 1H) 418.1 (−) 13

1.6-1.8 (m, 2H), 2.85-3.05 (m, 2H), 7.6 (d, 2H), 7.65-8.0 (m, 7H) 374.1(−) 14

1.4-2.1 (m, 4H), 3.95 (t, 1H), 7.5 (d, 2H), 7.69 (d, 2H), 7.83 (d, 2H),7.92 (d, 2H) 433.9 (+) 15

0.7-1.5 (m, 3H), 1.8-2.05 (m, 2H), 3.7-3.95 (m, 2H), 4.4-4.6 (m, 1H),6.9-7.2 (m, 4H), 7.45-7.78 (m, 9H), 8.4 (d, 1H) 510.0 (+) 16

1.55-2.1 (m, 6H), 2.8-3.05 (m, 2H), 3.2-3.4 (m, 4H), 6.65 (d, 2H),7.5-7.9 (m, 6H) 411.1 (+) 17

1.6-2.2 (m, 6H), 3.15-3.4 (m, 4H), 3.8-4.1 (m, 1H), 6.55 (d, 2H), 7.62(d, 2H), 7.75 (s, 4H), 7.9-8.1 (b, 1H) 455.1 (+) 18

0.8 (d, 3H), 0.9 (d, 3H), 1.85-2.1 (m, 1H), 3.3-3.5 (m, 1H), 7.55 (d,2H), 7.6-7.7 (m, 1H), 7.8 (d, 2H), 7.82 (d, 2H), 7.9 (d, 2H) 404.1 (+)19

0.8 (d, 3H), 0.9 (d, 3H), 1.85-2.1 (m, 5H), 3.2-3.35 (m, 4H), 3.36-3.5(m, 1H), 6.62 (d, 2H), 7.5 (dd, 1H), 7.6 (d, 2H), 7.7 (d, 2H), 7.82 (d,2H) 437.2 (−) 20

1.28 (d, 1.5H), 1.35 (d, 1.5H), 2.9-3.6 (m, 6H), 7.25-7.8 (m, 8H) 402.1(−) 21

— 710.9 (−) 22

0.88 (d, 1.5H), 0.95 (d, 1.5H), 1.9-2.1 (m, 4H), 3.3-3.4 (m, 5H), 6.63(d, 2H), 7.55-7.9 (m, 7H) 409.2 (−) 23

0.95, 1.05 (d, 6H), 2.07-2.32 (m, 1H), 4.07-4.3 (m, 1H), 7.35-7.59 (m,3H), 7.67-7.82 (m, 4H), 8.0 (d, 2H). 332.1 (−) 24

— 364.2 (−) 25

0.98 (d, 3H), 2.0-2.15 (m, 1H), 2.9-3.05 (m, 1H), 3.1-3.2 (m, 1H),3.25-3.5 (m, 3H), 7.2 (dd, 1H), 7.4 (d, 2H), 7.5 (d, 2H), 7.6 (d, 2H),7.7 (d, 2H) 432.1 (+)

Pharmacological Examples

[0250] Preparation and determination of the enzymatic activity of thecatalytic domain of human stromelysin and of neutrophil collagenase.

[0251] The two enzymes—stromelysin (“MMP-3”) and neutrophil collagenase(“MMP-8”)—were prepared according to Ye et al., 31 BIOCHEMISTRY 11231(1992). For the measurement of the enzyme activity or of the enzymeinhibitor action, 70 μl of buffer solution and 10 μl of enzyme solutionare incubated for 15 minutes with 10 μl of a 10% strength (v/v) aqueousdimethyl sulfoxide solution which optionally contains the enzymeinhibitor. After addition of 10 μl of a 10% strength (v/v) aqueousdimethyl sulfoxide solution which contains 1 mmol/l of the substrate,the enzyme reaction is monitored by fluorescence spectroscopy (328 nm(ex)/393 nm(em)).

[0252] The enzyme activity is shown as extinction increase/minute. TheIC₅₀ values listed in Table 2 are determined as those inhibitorconcentrations which in each case lead to a 50% inhibition of theenzyme.

[0253] The buffer solution contains 0.05% Brij (Sigma, Deisenhofen,Germany) and 0.1 mol/l of tris/HCl, 0.1 mol/l of NaCl, 0.01 mol/l ofCaCl₂ and 0.1 mol/l of piperazine-N,N′-bis[2-ethanesulfonic acid](pH=6.5).

[0254] The enzyme solution contains 5 μg/ml of one of the enzyme domainsprepared according to Ye et al. The substrate solution contains 1 mmol/lof the fluorogenic substrate(7-methoxycoumarin4-yl)acetyl-Pro-Leu-Gly-Leu-3-(2′,4′-dinitrophenyl)-L-2,3-diaminopropionyl-Ala-Arg-NH₂(Bachem, Heidelberg, Germany). TABLE 2 Neutrophil collagenase IC₅₀Example No. Stromelysin IC₅₀ (M) (M)  1 6 × 10⁻⁹ 1 × 10⁻⁹  2 5 × 10⁻⁶ 2× 10⁻⁷  3 1 × 10⁻⁷ 7 × 10⁻⁹  4 5 × 10⁻⁷ 6 × 10⁻⁸  5 1 × 10⁻⁷ 5 × 10⁻⁹  63 × 10⁻⁸ 3 × 10⁻⁹ 18 1 × 10⁻⁵ 1 × 10⁻⁶ 19 5 × 10⁻⁹ 2 × 10⁻⁹ 20 8 × 10⁻⁹2 × 10⁻⁹ 22 2 × 10⁻⁸ 2 × 10⁻⁸ 24 4 × 10⁻⁷ 3 × 10⁻⁸ 25 3 × 10⁻⁹ 2 × 10⁻⁹

[0255] Preparation and determination of the enzymatic activity of thecatalytic domain of aggrecanase using rat chondrosarcoma cells:

[0256] For the generation of the as yet not identified “aggrecanase”activity, rat chondrosarcoma cells (RCS) were used. Lark et al.; 270 J.BIOL. CHEM. 2550 (1995). These cells were inoculated into 96-well cellculture plates precoated with poly-L-lysine (80,000 cells/well). Afterstimulation of the RCS cells with retinoic acid (0.67 μM) and anincubation time of 47 hours (h) at 37° C. and 5% CO₂, these cellsgenerate the “aggrecanase” activity. The test substance compound 1 wasthen preincubated for 1 h in the “aggrecanase”-containing cell culturesupernatant before 5 μg of eucaryotic rAgg1_(mut) (Buttner et al., 333BIOCHEM. J. 159 (1998); Hughes et al., 272 J. BIOL. CHEM. 20269 (1997))were added for the detection of the “aggrecanase” cleavage activity inthe cell culture supernatant of the RCS cells. After an incubation timeof 4 h, the cell culture supernatant was removed and the cleavageproducts of the rAgg1_(mut) fusion proteins generated by the“aggrecanase” activity were detected by means of SDS-polyacrylamide gelelectrophoresis and Western Blot analyses with the monoclonal antibodyBC-3. Hughes et al., 305 BIOCHEM. J. 799 (1995). The action of thecompound 1 was seen in the lowering of the BC-3 reactive cleavageproducts. The less cleaved rAgg1_(mut) was detected, the moreefficacious was the tested compound of the formula I.

[0257] The IC₅₀ values listed in Table 3 are determined as thoseinhibitor concentrations which in each case led to a 50% inhibition ofthe enzyme aggrecanase. TABLE 3 Example No. Aggrecanase IC₅₀  1 0.6 10⁻⁶M  2 79 10⁻⁶ M  3 22 10⁻⁶ M  4 12 10⁻⁶ M  5 25 10⁻⁶ M  6 2.4 10⁻⁶ M  729 10⁻⁹ M  8 15 10⁻⁶ M 10 2.1 10⁻⁶ M 12 50 10⁻⁶ M 13 50 10⁻⁶ M 14 5510⁻⁶ M 15 67 10⁻⁶ M 16 28 10⁻⁶ M 17 69 10⁻⁶ M 18 60 10⁻⁶ M 20 4.7 10⁻⁶ M21 0.52 10⁻⁶ M 22 8.3 10⁻⁶ M

[0258] The invention may be embodied in other specific forms and thoseskilled in the art will recognize that various changes and modificationscan be made without departing from the spirit or essentialcharacteristics thereof. The present embodiment is, therefore,considered in all respects as illustrative and not restrictive.Embodiments are measured by the scope of the appended claims rather thanby the foregoing description, and all changes which come within themeaning and range of equivalency of the claims are therefore intended tobe embraced therein.

We claim:
 1. A compound of formula I

 a stereoisomeric form thereof, or a physiologically tolerable saltthereof, where (A.) R¹ is
 1. phenyl;
 2. phenyl, which is mono- ordisubstituted by 2.1 (C₁-C₆)—alkyl, 2.4. hydroxyl, 2.3.(C₁-C₆)—alkyl—C(O)—O—, 2.4. (C₁-C₆)—alkyl—O—, 2.5.(C₁-C₆)—alkyl—O—(C₁-C₄)—alkyl—O—, 2.6. halogen, 2.7. —CF₃, 2.8. —CN,2.9. —NO₂, 2.10. HO—C(O)—, 2.11. (C₁-C₆)—alkyl—O—C(O)—, 2.12.methylenedioxo, 2.13. R⁴—(R⁵)N—C(O)—, 2.14. R⁴—(R⁵)N—, or 2.15 aheteroaromatic described under A.3.1 to A.3.16;
 3. a heteroaromaticdescribed under A.3.1 to A.3.16, which is unsubstituted or substitutedby one or more radicals described under A.2.1 to A.2.15, 3.1. pyrrole,3.2. pyrazole, 3.3. imidazole, 3.4. triazole, 3.5. thiophene, 3.6.thiazole, 3.7. oxazole, 3.8. isoxazole, 3.9. pyridine, 3.10. pyrimidine,3.11. pyrrolidine, 3.12. indole, 3.13. benzothiophene, 3.14.benzimidazole, 3.15. benzoxazole, or 3.16. benzothiazole; or 4.—O—(C₁-C₆)—alkyl; (B.) R², R⁴ and R⁵ independently of one another areidentical or different and are
 1. a hydrogen atom;
 2. (C₁-C₆)—alkyl-; 3.HO—C(O)—(C₁-C₆)—alkyl-;
 4. phenyl—(CH₂)_(n)—, in which phenyl isunsubstituted or mono- or disubstituted with radicals described underA.2.1 to A.2.15, or is substituted by —NH—C(O)—(C₁-C₃)—alkyl, and n isthe integer zero, 1, or 2;
 5. picolyl; or
 6. R⁴ and R⁵, together withthe nitrogen to which they are bonded, form a 4- to 7-membered ring, andthe ring is unsubstituted, or a carbon atom in the ring is replaced by—O—, —S—, or —NH—, or two adjacent carbon atoms of the 4- to 7-memberedring are part of a benzyl radical; (C.) R and R³ are identical ordifferent and are
 1. a hydrogen atom;
 2. (C₁-C₁₀)—alkyl-, in which alkylis unsubstituted or monosubstituted by —OH;
 3. (C₂-C₁₀)—alkenyl-, inwhich alkenyl is linear or branched;
 4. R²—O—(C₁-C₆)—alkyl-; 5.R²—S(O)_(n)—(C₁-C₆)—alkyl-, where n is the integer zero, 1, or 2; 6.R²—S(O)(═NH)—(C₁-C₆)—alkyl-;
 7. a radical of formula IIo

 in which n is the integer zero, 1, or 2, and W is a nitrogen, oxygen,or sulfur atom;
 8. phenyl—(CH₂)_(m)—, in which m is the integer zero, 1,2, 3, 4, 5, or 6, wherein the —(CH₂)_(m)— chain is unsubstituted ormonosubstituted by —OH, and wherein phenyl is unsubstituted or mono- ordisubstituted by 8.1 radicals described under A.2.1 to A.2.15, 8.2—O—(CH₂)_(m)—phenyl, in which phenyl is unsubstituted or mono- ordisubstituted with radicals described under A.2.1 to A.2.15, and m isthe integer zero, 1, 2, 3, 4, 5, or 6, 8.3 —C(O)—(CH₂)_(m)—phenyl, inwhich phenyl is defined under C.8.2;
 9. heteroaryl—(CH₂)_(m)—, in whichheteroaryl is defined under A.3.1 to A.3.16, m is defined under C.8, the—(CH₂)_(m)— chain is unsubstituted or monosubstituted by —OH, andheteroaryl is unsubstituted or mono- or disubstituted by 9.1 radicalsdescribed under A.2.1 to A.2.15, 9.2 —CH(O), 9.3 —SO₂—phenyl, in whichphenyl is unsubstituted or substituted as defined under C.8.2 or C.8.3,9.4 —O—(CH₂)_(m)—phenyl;
 10. —(CH₂)_(m)—P(O)(OH)—(C₁-C₃)—alkyl, in whichm is defined under C.8;
 11. a characteristic radical of an amino acid;12. R⁶—C(O)—(C₀-C₆)—alkyl- in which R⁶ is 12.1. a hydrogen atom, 12.2.(C₁-C₆)—alkyl-, 12.3. phenyl, which is unsubstituted or substituted withone or more radicals described under A.2.1 to A.2.15, 12.4. heteroaryl,which is defined under A.3.1 to A.3.16, and is unsubstituted orsubstituted with one or more radicals described under A.2.1 to A.2.15,or is substituted by —(C₁-C₄)—alkyl—COOH, 12.5. —OH, 12.6. —OR², inwhich R² has the meaning described under B.1 to B.6, 12.7. —NR⁴—(R⁵), inwhich R⁴ and R⁵ are defined under B.1 to B.6, 12.8.heteroaryl—(CH₂)_(m)—NH—, in which heteroaryl is defined under A.3.1 toA.3.16, and is unsubstituted or substituted with one or more radicalsdescribed under A.2.1 to A.2.15, and m is defined under C.8, 12.9.R⁴—(R⁵)N—NH—, in which R⁴ and R⁵ are defined under B.1 to B.6, 12.10.HO—C(O)—CH(R³)—NH—, in which R³ is defined under C.1 to C.11; 13.—(CH₂)p—N(R⁹)(R¹⁰), in which p is an integer zero, 1, 2, 3, or 4, inwhich R⁹ and R¹⁰ are identical or different and are 13.1. a hydrogenatom, 13.2. phenyl—(CH₂)_(m)—, in which phenyl is unsubstituted or mono-or disubstituted with radicals described under A.2.1 to A.2.15, and m isthe integer zero, 1, 2, or 3, 13.3. R^(x)—C(O)—, in which R^(x) is 3.1(C₁-C₆)—alkyl-, 3.2 (C₂-C₆)—alkenyl-, 3.3 phenyl—(CH₂)_(m)—, in whichphenyl is unsubstituted or mono- or disubstituted with radicalsdescribed under A.2.1 to A.2.15, and m is the integer zero, 1, 2, or 3,or 3.4 heteroaryl—(CH₂)_(m)—, in which heteroaryl is defined under A.3.1to A.3.16, 13.4. R^(x)—O—C(O)—, in which R^(x) is defined under C.13.3,13.5. R^(x)—CH(NH₂)—C(O)—, in which R^(x) is defined under C.13.3, 13.6.R⁸—N(R⁷)—C(O)—, in which R⁸ is 6.1 a hydrogen atom 6.2 (C₁-C₆)—alkyl-,6.3 phenyl—(CH₂)_(m), in which phenyl is unsubstituted or mono- ordisubstituted with radicals described under A.2.1 to A.2.15, and m isthe integer zero, 1, 2, or 3, or 6.4 heteroaryl—(CH₂)_(m), in whichheteroaryl is defined under A.3.1 to A.3.16, and is unsubstituted orsubstituted with one or more radicals described under A.2.1 to A.2.15, mis the integer zero, 1, 2, or 3, and in which R⁷ is a hydrogen atom or(C₁-C₆)—alkyl-, or in which R⁷ and R⁸, together with the nitrogen atomto which they are bonded, form a 4- to 7-membered ring, and the ring isunsubstituted or a carbon atom in the ring is replaced by —O—, —S—, or—NH—, 13.7. R^(x)—SO₂—, in which R^(x) is defined under C.13.3, 13.8.R^(x)—NH—C(═NR⁷), in which R^(x) is defined under C.13.3 and R⁷ isdefined under C.13.6.4, or R^(x) and R⁷ are 8.1 (C₁-C₆)—alkyl—C(O)—, 8.2—NO₂ or 8.3 —SO₂—(CH₂)_(q)—phenyl, in which phenyl is unsubstituted ormono- or disubstituted with radicals described under A.2.1 to A.2.15,and q is the integer zero, 1, 2, or 3, 13.9.—SO₂—(CH₂)_(q)—phenyl-phenyl, in which each phenyl independently isunsubstituted or mono- or disubstituted with radicals described underA.2.1 to A.2.15, and q is the integer zero, 1, 2, or 3, or 13.10. aradical of formula IIp

 in which m is the integer zero, 1, 2, or 3, and W is a nitrogen atom orsulfur atom, or R⁹ and R¹⁰, together with the nitrogen atom to whichthey are bonded, form a ring chosen from radicals of the subformulae IIato IIn,

 where r is the integer 1 or 2, R¹¹ is a radical described under A.2.1to A.215, R⁷ is defined under C.13.6.4, and m is defined under C.13.2,and a carbon atom in the ring is replaced by zero or one heterospecieschosen from oxygen, sulfur, or nitrogen atom which is unsubstituted ormonosubstituted with R²;
 14. —OH;
 15. ═O;
 16. (C₁-C₆)—alkyl-; or in thecompound of formula I, a —C(R)(R³)— radical is optionally replaced by—NH— or —NR²— in which R² is defined under B.1 to B.6; (D.) t is aninteger 1, 2, 3, or 4; (E.) R² and R³ together form a ring with anexocyclic phosphinic or phosphonic acid radical of the subformula II

 in which r is the integer zero, 1, 2, or 3, and one carbon atom in thering of the radical of subformula II is replaced by zero or oneheterospecies chosen from —O—, —S—, or —(R⁷)N—, in which R⁷ is
 1. ahydrogen atom;
 2. (C₁-C₆)—alkyl;
 3. phenyl, in which phenyl isunsubstituted or substituted with one or more radicals described underA.2.1 to A.2.15;
 4. benzyl, in which benzyl is unsubstituted orsubstituted with one or more radicals described under A.2.1 to A.2.15;or R²N—C(═NH)— where R² has the meaning described under B.1 to B.6, andthe carbon atoms in the ring of the subformula II are unsubstituted ormono- or polysubstituted by (C₁-C₆)—alkyl-, phenyl-, phenyl—(CH₂)_(m)—or HO—, or combinations thereof; (F.) U is —SO₂— or —CO—; (G.) Y¹ and Y²are identical or different and independently of one another are a) ahydrogen atom; b) —OH; c) —(C₁-C₄)—alkyl, in which alkyl is linear orbranched; d) —(CH₂)_(u)—phenyl, in which u is zero or 1; e)—O—(C₁-C₄)—alkyl, in which alkyl is linear or branched; or f)—O—(CH₂)_(s)—phenyl, in which s is zero or 1; (H.) A is a) a covalentbond; b) —O—; c) —CH═CH—; or d) —C≡C—; (I.) B is a) —(CH₂)_(m)—, inwhich m is defined under C.13.2; b) —O—(CH₂)_(p), in which p is aninteger from 1 to 5; or c) —CH═CH—; and (J.) X is —CH═CH—, an oxygenatom, or a sulfur atom.
 2. The compound of formula I as claimed in claim1, wherein R¹ is
 1. phenyl;
 2. phenyl which is monosubstituted by 2.1.(C₁-C₆)—alkyl-, 2.2. —OH, 2.3. —C(O)—OH, 2.4. —O—(C₁-C₆)—alkyl, 2.5.pyrrolidone, 2.6. halogen, or 2.7. —CF₃; or
 3. —O—(C₁-C₆)—alkyl; R², R⁴and R⁵ are identical or different and are a hydrogen atom or(C₁-C₆)—alkyl-; R is a hydrogen atom; R³ is
 1. (C₁-C₆)—alkyl-, in whichalkyl is unsubstituted or monosubstituted by —OH, 2.R²—S(O)_(n)—(C₁-C₆)—alkyl-, in which R² is (C₁-C₆)—alkyl- orphenyl—(CH₂)_(n)—, and n is the integer zero or 1;
 3. —(CH₂)_(m)—phenyl,in which phenyl is unsubstituted or mono- or disubstituted with radicalsdescribed under A.2.1 to A.2.15 in claim 1, the —(CH₂)_(m)— chain isunsubstituted or monosubstituted by —OH, and m is the integer 1, 2, 3,4, or 5;
 4. —(CH₂)_(m)—heteroaryl, in which heteroaryl has the meaningmentioned under A.3.3, A.3.5, A.3.6, A.3.9, or A.3.11 in claim 1, and isunsubstituted or substituted with one or more radicals described underA.2.1 to A.2.15 in claim 1, the —(CH₂)_(m)— chain is unsubstituted ormonosubstituted by —OH, and m is the integer 1, 2, 3, or 4;
 5. acharacteristic radical of an amino acid;
 6. —(CH₂)_(p)—N(R⁹)(R¹⁰), inwhich p is the integer zero, 1, or 2 in which R⁹ and R¹⁰ are identicalor different and are a hydrogen atom or —SO₂—(CH₂)_(q)—phenyl-phenyl, inwhich each phenyl independently is unsubstituted or mono- ordisubstituted with radicals described under A.2.1 to A.2.15 in claim 1,and q is the integer zero, 1, 2, or 3; or
 7. R⁶—C(O)—, in which R⁶ is7.1. —OH, 7.2. R²O—, in which R² is defined under B.1 to B.6 in claim 1,or 7.3. R⁴—(R⁵)N—, in which R⁴ and R⁵ are defined under B.1 to B.6 inclaim 1;
 8. a hydrogen atom;
 9. —OH;
 10. ═O; or
 11. (C₁-C₆)—alkyl-; orin the compound of formula I, a —C(R)(R³)— radical is optionallyreplaced by —NH— or—NR²—, in which R² is defined under B.1 to B.6 inclaim 1; and t is an integer 1, 2, 3, or 4; U is —SO₂—; Y¹ is —OH; Y² isa) —O—(C₁-C₄)—alkyl, in which alkyl is linear or branched, b) —OH, or c)—(C₁-C₄)—alkyl, in which alkyl is linear or branched; A is a covalentbond or —O—; B is a covalent bond or —(C₁-C₄)—alkyl; and X is —CH═CH—.3. A compound of formula I as claimed in claim 1, wherein R¹ is phenylwhich is monosubstituted by halogen; R² is a hydrogen atom; R is ahydrogen atom; R³ is
 1. (C₁-C₄)—alkyl-;
 2. -phenyl, in which phenyl isunsubstituted or mono- or disubstituted by —CF₃ or —COOH;
 3. a hydrogenatom;
 4. —OH; or
 5. —NH—SO₂—phenyl-phenyl, in which each phenylindependently is unsubstituted or substituted by one ore more identicalor different halogen atoms; t is an integer 1, 2, 3, or 4; U is —SO₂—;Y¹ and Y² are identical or different and are —OH or —O—CH₃; A is acovalent bond; B is a covalent bond or —(CH₂)_(o)—, in which o is 1, 2,or 3; and X is—CH═CH—.
 4. A compound of formula I as claimed in claim 1,chosen from(R)-[1-(4′-chlorobiphenyl4-sulfonylamino)-2-methylpropyl]phosphonicacid,dimethyl-[3-(4′-chlorobiphenyl4-sulfonylamino)-1-hydroxy-3-(4-trifluoromethylphenyl)propyl]phosphonate,[1-(4′-chlorobiphenyl4-sulfonylamino)-3-methylbutyl]-phosphonic acid,monoethyl-(R,S)-[1-(4′-chlorobiphenyl4-sulfonylamino)-1-phenylmethyl]phosphonate,a stereoisomeric form of said compound, and a physiologically tolerablesalt of any of the foregoing.
 5. A process for preparing a compound offormula I as described in claim 1, comprising the step of: reacting anaminophosphinic or -phosphonic acid of formula III,

 in which R², Y¹, Y², t, R, and R³ are as defined in formula I, with asulfonic acid or carbonyl derivative of formula IV

 in which R¹, A, X, U, and B are as defined in formula I, and Z is ahalogen atom, imidazolyl, or —OR⁸, in which R⁸ is a hydrogen atom,(C₁-C₆)—alkyl, phenyl or benzyl, wherein said alkyl, phenyl, or benzylis independently unsubstituted or substituted, in the presence of a baseto give a compound of formula I.
 6. The process as claimed in claim 5,wherein the reacting step is performed in the presence of a dehydratingagent.
 7. The process as claimed in claim 5, wherein when the compoundof formula I comprises an enantiomeric form, said process furthercomprising at least one of the following steps: forming a salt of saidcompound with an enantiomerically pure acid or base, or chromatographingsaid compound on a chiral stationary phase, or derivatizating saidcompound with a chiral enantiomerically pure compound, and separatingdiastereomers thus obtained, and removing chiral auxiliary groups. 8.The process as claimed in claim 5, further comprising the step of:isolating the compound of formula I in free form.
 9. The process asclaimed in claim 5, further comprising the step of: converting thecompound of formula I into at least one physiologically tolerable salt.10. A process for preparing a compound of formula I, as described inclaim 1, comprising the steps of: reacting an aminophosphinic or-phosphonic acid ester of formula V

 in which R², R, R³, t, and Y² are as defined in formula I and R⁸ is ahydrogen atom, (C₁-C₆)—alkyl, phenyl, or benzyl, wherein said alkyl,phenyl, or benzyl is independently unsubstituted or substituted, with asulfonic acid or carbonyl derivative of formula IV

 in which R¹, A, X, U, and B are as defined in formula I, and Z is ahalogen atom, imidazolyl, or —OR, in which R⁸ is a hydrogen atom,(C₁-C₆)—alkyl, phenyl, or benzyl, wherein said alkyl, phenyl, or benzylis independently unsubstituted or substituted, to give a compound offormula VI

 and converting the compound of formula VI with removal of the radicalR⁸ into a compound of formula I.
 11. The process as claimed in claim 10wherein when said compound of formula I occurs in enantiomeric form,said process further comprising at least one of the following steps:forming a salt of said compound with an enantiomerically pure acid orbase, or chromatographing said compound on a chiral stationary phase, orderivatizating said compound with a chiral enantiomerically purecompound, and separating diastereomers thus obtained, and removingchiral auxiliary groups.
 12. The process as claimed in claim 10, furthercomprising the step of: isolating the compound of formula I in freeform.
 13. The process as claimed in claim 10, further comprising thestep of: converting said compound of formula I into at least onephysiologically tolerable salt.
 14. A process for preparing a compoundof formula I, as described in claim 1, comprising the steps of: reactinga compound of formula VII

 where n is the integer zero, 1, or 2, Y² is as defined under G. inclaim 1, and R⁸ is a hydrogen atom, (C₁-C₆)—alkyl, phenyl, or benzyl,wherein said alkyl, phenyl, or benzyl is independently unsubstituted orsubstituted, with the aid of a protective group E to give a compound offormula VIII,

 reacting the compound of formula VIII with a compound of formula IV

 in which R¹, A , X, U, and B are as defined in formula I and Z is ahalogen atom, imidazolyl, or —OR⁸, in which R⁸ is a hydrogen atom,(C₁-C₆)—alkyl, phenyl, or benzyl, wherein said alkyl, phenyl, or benzylis independently unsubstituted or substituted, to yield a compound offormula IX

 and then converting the compound of formula IX, with removal of theprotective group E and of the radical R⁸, into the compound of formulaI.
 15. The process as claimed in claim 14, wherein when said compound offormula I occurs in enantiomeric form, said process further comprisingat least one of the following steps: forming a salt of said compoundwith an enantiomerically pure acid or base, or chromatographing saidcompound on a chiral stationary phase, or derivatizating said compoundwith a chiral enantiomerically pure compound, and separatingdiastereomers thus obtained, and removing chiral auxiliary groups. 16.The process as claimed in claim 14, further comprising the step of:isolating the compound of formula I in free form.
 17. The process asclaimed in claim 14, further comprising the step of: converting thecompound of formula I into at least one physiologically tolerable salt.18. A pharmaceutical composition for prophylaxis or therapy of adisorder in a human or animal patient, said disorder involving, at leastin part, an increased activity of matrix-degrading metalloproteinase,comprising an amount efficacious for said prophylaxis or therapy, of atleast one compound of formula I, a stereoisomeric form thereof, aphysiologically tolerable salt thereof, or a mixture of any of theforegoing, together with at least one pharmaceutically suitable andphysiologically tolerable excipient; said compound of formula I being:

 a stereoisomeric form thereof, or a physiologically tolerable saltthereof, where (A.) R¹ is
 1. phenyl;
 2. phenyl, which is mono- ordisubstituted by 2.1. (C₁-C₆)—alkyl, 2.2. hydroxyl, 2.3.(C₁-C₆)—alkyl—C(O)—O—, 2.4. (C₁-C₆)—alkyl—O—, 2.5.(C₁-C₆)—alkyl—O—(C₁-C₄)—alkyl—O—, 2.6. halogen, 5 2.7. —CF₃, 2.8. —CN,2.9. —NO₂, 2.10. HO—C(O)—, 2.11. (C₁-C₆)—alkyl—O—C(O)—, 2.12.methylenedioxo, 2.13. R⁴—(R⁵)N—C(O)—, 2.14. R⁴—(R⁵)N—, or 2.15. aheteroaromatic described under A.3.1 to A.3.16;
 3. a heteroaromaticdescribed under A.3.1 to A.3.16, which is unsubstituted or substitutedby one or more radicals described under A.2.1 to A.2.15, 3.1. pyrrole,3.2. pyrazole, 3.3. imidazole, 3.4. triazole, 3.5. thiophene, 3.6.thiazole, 3.7. oxazole, 3.8. isoxazole, 3.9. pyridine, 3.10. pyrimidine,3.11. pyrrolidine, 3.12. indole, 3.13. benzothiophene, 3.14.benzimidazole, 3.15. benzoxazole, or 3.16. benzothiazole; or 4.—O—(C₁-C₆)—alkyl; (B.) R², R⁴ and R⁵ independently of one another areidentical or different and are
 1. a hydrogen atom;
 2. (C₁-C₆)—alkyl-; 3.HO—C(O)—(C₁-C₆)—alkyl-;
 4. phenyl—(CH₂)_(n)—, in which phenyl isunsubstituted or mono- or disubstituted with radicals described underA.2.1 to A.2.15, or is substituted by —NH—C(O)—(C₁-C₃)—alkyl, and n isthe integer zero, 1, or 2;
 5. picolyl; or
 6. R⁴ and R⁵, together withthe nitrogen to which they are bonded, form a 4- to 7-membered ring, andthe ring is unsubstituted, or a carbon atom in the ring is replaced by—O—, —S—, or —NH—, or two adjacent carbon atoms of the 4- to 7-memberedring are part of a benzyl radical; (C.) R and R³ are identical ordifferent and are
 1. a hydrogen atom;
 2. (C₁-C₁₀)—alkyl-, in which alkylis unsubstituted or monosubstituted by —OH;
 3. (C₂-C₁₀)—alkenyl-, inwhich alkenyl is linear or branched;
 4. R²—O—(C₁-C₆)—alkyl-; 5.R²—S(O)_(n)—(C₁-C₆)—alkyl-, where n is the integer zero, 1, or 2; 6.R²—SO)(═NH)—(C₁-C₆)—alkyl-;
 7. a radical of formula IIo

 in which n is the integer zero, 1, or 2, and W is a nitrogen, oxygen,or sulfur atom;
 8. phenyl—(CH₂)_(m)—, in which m is the integer zero, 1,2, 3, 4, 5, or 6, wherein the —(CH₂)_(m)— chain is unsubstituted ormonosubstituted by —OH, and wherein phenyl is unsubstituted or mono- ordisubstituted by 8.1 radicals described under A.2.1 to A.2.15, 8.2—O—(CH₂)_(m)—phenyl, in which phenyl is unsubstituted or mono- ordisubstituted with radicals described under A.2.1 to A.2.15, and m isthe integer zero, 1, 2, 3, 4, 5, or 6, 8.3 —C(O)—(CH₂)_(m)—phenyl, inwhich phenyl is defined under C.8.2;
 9. heteroaryl—(CH₂)_(m)—, in whichheteroaryl is defined under A.3.1 to A.3.16, m is defined under C.8, the—(CH₂)_(m)— chain is unsubstituted or monosubstituted by —OH, andheteroaryl is unsubstituted or mono- or disubstituted by 9.1 radicalsdescribed under A.2.1 to A.2.15, 9.2 —CH(O), 9.3 —SO₂—phenyl, in whichphenyl is unsubstituted or substituted as defined under C.8.2 or C.8.3,9.4 —O—(CH₂)_(m)—phenyl;
 10. —(CH₂)_(m)—P(O)(OH)—(C₁-C₃)—alkyl, in whichm is defined under C.8;
 11. a characteristic radical of an amino acid;12. R⁶—C(O)—(C₀-C₆)—alkyl- in which R⁶ is 12.1. a hydrogen atom, 12.2.(C₁-C₆)—alkyl-, 12.3. phenyl, which is unsubstituted or substituted withone or more radicals described under A.2.1 to A.2.15, 12.4. heteroaryl,which is defined under A.3.1 to A.3.16, and is unsubstituted orsubstituted with one or more radicals described under A.2.1 to A.2.15,or is substituted by —(C₁-C₄)—alkyl—COOH, 12.5. —OH, 12.6. —OR², inwhich R² has the meaning described under B.1 to B.6, 12.7. —NR⁴—(R⁵), inwhich R⁴ and R⁵ are defined under B.1 to B.6, 12.8.heteroaryl—(CH₂)_(m)—NH—, in which heteroaryl is defined under A.3.1 toA.3.16, and is unsubstituted or substituted with one or more radicalsdescribed under A.2.1 to A.2.15, and m is defined under C.8, 12.9.R⁴—(R⁵)N—NH—, in which R⁴ and R⁵ are defined under B.1 to B.6, 12.10.HO—C(O)—CH(R³)—NH—, in which R³ is defined under C.1 to C.11; 13.—(CH₂)_(p)—N(R⁹)(R¹⁰), in which p is an integer zero, 1, 2, 3, or 4, inwhich R⁹ and R¹⁰ are identical or different and are 13.1 a hydrogenatom, 13.2. phenyl—(CH₂)_(m)—, in which phenyl is unsubstituted or mono-or disubstituted with radicals described under A.2.1 to A.2.15, and m isthe integer zero, 1, 2, or 3, 13.3. R^(x)—C(O)—, in which R^(x) is 3.1(C₁-C₆)—alkyl-, 3.2 (C₂-C₆)—alkenyl-, 3.3 phenyl—(CH₂)_(m)—, in whichphenyl is unsubstituted or mono- or disubstituted with radicalsdescribed under A.2.1 to A.2.15, and m is the integer zero, 1, 2, or 3,or 3.4 heteroaryl—(CH₂)_(m)—, in which heteroaryl is defined under A.3.1to A.3.16, 13.4. R^(x)—O—C(O)—, in which R^(x) is defined under C.13.3,13.5. R^(x)—CH(NH₂)—C(O)—, in which R^(x) is defined under C.13.3, 13.6.R⁸—N(R⁷)—C(O)—, in which R⁸ is 6.1 a hydrogen atom 6.2 (C₁-C₆)—alkyl-,6.3 phenyl—(CH₂)_(m), in which phenyl is unsubstituted or mono- ordisubstituted with radicals described under A.2.1 to A.2.15, and m isthe integer zero, 1, 2, or 3, or 6.4 heteroaryl—(CH₂)_(m), in whichheteroaryl is defined under A.3.1 to A.3.16, and is unsubstituted orsubstituted with one or more radicals described under A.2.1 to A.2.15, mis the integer zero, 1, 2, or 3, and in which R⁷ is a hydrogen atom or(C₁-C₆)—alkyl-, or in which R⁷ and R⁸, together with the nitrogen atomto which they are bonded, form a 4- to 7-membered ring, and the ring isunsubstituted or a carbon atom in the ring is replaced by —O—, —S—, or—NH—, 13.7. R^(x)—SO₂—, in which R^(x) is defined under C.13.3, 13.8.R^(x)—NH—C(═NR⁷), in which R^(x) is defined under C.13.3 and R⁷ isdefined under C.13.6.4, or R^(x) and R⁷ are 8.1 (C₁-C₆)—alkyl—C(O)—, 8.2—NO₂ or 8.3 —SO₂—(CH₂)_(q)—phenyl, in which phenyl is unsubstituted ormono- or disubstituted with radicals described under A.2.1 to A.2.15,and q is the integer zero, 1, 2, or 3, 13.9.—SO₂—(CH₂)_(q)—phenyl-phenyl, in which each phenyl independently isunsubstituted or mono- or disubstituted with radicals described underA.2.1 to A.2.15, and q is the integer zero, 1, 2, or 3, or 13.10. aradical of formula IIp

 in which m is the integer zero, 1, 2, or 3, and W is a nitrogen atom orsulfur atom, or R⁹ and R¹⁰, together with the nitrogen atom to whichthey are bonded, form a ring chosen from radicals of the subformulae IIato IIn,

 where r is the integer 1 or 2, R¹¹ is a radical described under A.2.1to A.2.15, R⁷ is defined under C.13.6.4, and m is defined under C.13.2,and a carbon atom in the ring is replaced by zero or one heterospecieschosen from oxygen, sulfur, or nitrogen atom which is unsubstituted ormonosubstituted with R²;
 14. —OH;
 15. ═O;
 16. (C₁-C₆)—alkyl-; or in thecompound of formula I, a —C(R)(R³)— radical is optionally replaced by—NH— or —NR²— in which R² is defined under B.1 to B.6; (D.) t is aninteger 1, 2, 3, or 4; (E.) R² and R³ together form a ring with anexocyclic phosphinic or phosphonic acid radical of the subformula II

 in which r is the integer zero, 1, 2, or 3, and one carbon atom in thering of the radical of subformula II is replaced by zero or oneheterospecies chosen from —O—, —S—, or —(R⁷)N—, in which R⁷ is
 1. ahydrogen atom;
 2. (C₁-C₆)—alkyl;
 3. phenyl, in which phenyl isunsubstituted or substituted with one or more radicals described underA.2.1 to A.2.15;
 4. benzyl, in which benzyl is unsubstituted orsubstituted with one or more radicals described under A.2.1 to A.2.15;or
 5. R²N—C(═NH)— where R² has the meaning described under B.1 to B.6,and the carbon atoms in the ring of the subformula II are unsubstitutedor mono- or polysubstituted by (C₁-C₅)—alkyl-, phenyl-,phenyl—(CH₂)_(m)— or HO—, or combinations thereof; (F.) U is —SO₂— or—CO—; (G.) Y¹ and Y² are identical or different and independently of oneanother are a) a hydrogen atom; b) —OH; c) —(C₁-C₄)—alkyl, in whichalkyl is linear or branched; d) —(CH₂)_(u)—phenyl, in which u is zero or1; e) —O—(C₁-C₄)—alkyl, in which alkyl is linear or branched; or f)—O—(CH₂)_(s)—phenyl, in which s is zero or 1; (H.) A is a) a covalentbond; b) —O—; c) —CH═CH—; or d) —C≡C—; (I.) B is a) —(CH₂)_(m)—, inwhich m is defined under C.13.2; b) —O—(CH₂)_(p), in which p is aninteger from 1 to 5; or c) —CH═CH—; and (J.) X is —CH═CH—, an oxygenatom, or a sulfur atom.
 19. A method for the prophylaxis or treatment ofa disorder in a human or animal patient, involving, at least in part, anincreased activity of at least one matrix-degrading metalloproteinase,said method comprising the step of administering to said patient anamount, efficiacious for said prophylaxis or therapy, of a compound offormula I as claimed in claim 1, a stereoisomeric form thereof, or aphysiologically tolerable salt thereof, or a combination of any of theforegoing.
 20. The method as claimed in claim 19, wherein said disorderis a degenerative joint disorder, chondrolysis after joint trauma, jointimmobilization, or a tom ligament, a disorder of the connective tissue,a periodontal disorder, a wound healing disorder, a chronic disorder ofthe locomotory apparatus, an arthropathy, a myalgia, a disorder of thebone metabolism, ulceration, atherosclerosis, stenosis, an inflammation,a carcinomatous disorder, tumor metastasis formation, cachexia, anorexiaor septic shock.
 21. The method as claimed in claim 19, wherein saiddisorder is osterorathrosis, spondylosis, collagenosis, or results fromjoint immobilization after meniscus or patella injury, or aninflammatory, immunologically or metabolically related acute or chronicarthritis.